Tox and Hound – Snakes! Why’d it have to be SNAKES?

Unless you suffer the over appreciated and never-ending summer of southern California, the warm weather season is winding down and fall is settling in. Though many will lament the end of iced coffees, sunny beaches, and carefree summer attire, for many toxicologists, we will quietly lament the end of snake season. Perhaps you were lucky enough to see a snake envenomation this summer and have some lingering questions? Or you are eager to prepare for next season? Maybe you just recognize that envenomations are the coolest part of toxicology and want to learn more. Look no further, your expert answers for snake envenomations are here.

In considering snakes, we first must define which snakes are under discussion. In the US, the most medically important snakes are the Vipers, specifically the Crotalids which include rattlesnakes (genus Crotalus and genus Sistrurus), copperheads and cottonmouths (genus Agkistrodon). Everything that follows applies to rattlesnakes, however copperheads and cottonmouths have similar presentations (often milder) and management. We won’t be discussing other venomous snakes, most notably the Elapids.

ID, please

Crotalids are identified by triangular shaped heads, vertically oriented elliptical pupils, front mobile fangs, and a single row (as opposed to a double row in non-venomous species) of scales on the undersurface. They are famous for a characteristic rattle, however juveniles may not yet have a rattle, and certain species (C. catalinensis) do not form rattles. Pit-like depressions behind the nostrils contain heat-seeking organs that assist in prey detection and inspire their common name: pit vipers. Although your ability to identify a snake species might impress me, if you are examining fangs, you have gotten way too close to the snake. Which brings me to the most important (and coolest) aspect of snakes: the venom. Rattlesnake venom is a formidable mixture of proteins, lipids, and carbohydrates, with enzymes including metalloproteinases, phospholipases, and hyaluronidases. The actions of the individual components of venom remain poorly understood, and venom content and effect can vary significantly between seasons. Hemotoxicity in the form of coagulopathy and thrombocytopenia, and local tissue damage are the primary clinical effects. Although neurotoxicity is typically associated with the Elapids, some neurotoxicity can occur with rattlesnake envenomation. This typically manifests as fasciculations or myokymia and is only seen in certain geographic areas.

by Howard Greller (Bronx Zoo)

People often have the impression that baby rattlesnakes are more dangerous than adults, offering the explanation that juveniles cannot yet control the dose of venom delivered (aka “premature envenomation”). Although this explanation is unlikely, anecdotally, we do find that juvenile rattlesnake envenomations sometimes result in more significant hemotoxicity without the accompanying local tissue findings. While in vitro venom studies can be difficult to interpret, there is at least some evidence showing increased activity of thrombin-like enzymes (responsible for coagulopathy) in the venom of juvenile rattlesnakes.1

by Meghan Spyres (San Diego Zoo)

Who gets bitten by rattlesnakes?

In the US, there are approximately 5000 native venomous snakebites each year.2 Historically, we thought most people bitten by snakes more or less had it coming. (Think of the rather derogatory “T’s” of snakebite. Historically, we called these ‘illegitimate bites,’ meaning the victim was aware of an impending encounter with the snake but did not attempt to avoid it. More recently, we refer to these bites as ‘intentional’ bites.. Think of people handling pet snakes, performing ceremonies with snakes, milking snakes to self-immunize (see The Dantastic Mr. Tox &Howard Episode 2 – Snakes on a Podcast with Dr. Michelle Ruha to hear an amazing story), drunk selfie attempts with snakes, picking up and moving snakes in the wild, and so on. These bites usually occur on the hands and upper extremities.3,4 In contrast, ‘unintentional’ bites involve situations in which people did not intend to interact with the snake. In previous decades, the majority of snakebites were indeed intentional.3,5 More recent epidemiologic data supports a significant reduction in intentional bites, with numbers quoted now closer to 20% of envenomations in a large study.4One part of the famous “T’s”, however holds true: of the intentional snake bites reported, the vast majority (>90%) occur in men. In the above study, ethanol intoxication was reported in only 8.4% of snake bites, however due to the method of data collection, this may represent an underestimate. Women and children do sustain snakebites, although those bites are usually unintentional and occur on the lower extremities.4Snake bites tend to occur in the warmer months when both people and snakes are out of doors.5

Your patient thinks she was bitten by a rattlesnake. Is she going to die?

The short answer is no. Although rattlesnake envenomations are associated with significant morbidity, death by snakebite in the US is quite rare.2Patients typically present to EDs with pain and swelling to the envenomated extremity and normal vital signs, perhaps with pain-related tachycardia. Systemic toxicity is rare and may occur in the field prior to presentation. Early signs of systemic toxicity include vomiting and diarrhea, and be worried if you see either because hypotension and shock can develop soon after. Allergic reactions and anaphylaxis due to previous sensitization can also occur. (Yes, repeat offenders are a thing. Remember that guy who was attempting to immunize himself? He is not alone.)

Your patient will live to tell the tale. How do you treat her?

The first step is to determine if the patient was truly envenomated or if she suffered a ‘dry bite’. Up to 25% of pit viper bites do not result in venom delivery and are considered to be dry bites. A true envenomation is determined by the presence of hemotoxicity on labs or swelling on physical exam. The presence of either is indicative of a true envenomation. Labs to be drawn include a CBC to assess for thrombocytopenia, and a fibrinogen and/or a PT/INR (coagulopathy). Fibrinogen is preferred over PT because medications can alter the PT, and it is also prone to falsely elevated results. Some rattlesnakes such as the Southern Pacific can also cause rhabdomyolysis after envenomation, so checking a CK is usually a good idea.

On physical exam you are looking for erythema and edema. The puncture marks don’t help you much because they can be present in dry bites and can vary significantly. The strike of the bite itself can cause very localized erythema and edema, but changes extending beyond the bite site are evidence of a true envenomation. We typically look for swelling that extends beyond one major joint (forearm swelling after a hand envenomation, for example). Pain and tenderness are also important and are typically evidence of a true envenomation. If the physical exam is subtle, the lymph nodes can be checked for tenderness. Venom travels up the lymphatics, so when venom is present, tenderness can often be elicited in the groin with leg bites and in the axilla with arm bites as a marker of true envenomation.

If no initial signs of envenomation are evident, an observation period of 8-12 hours is recommended before diagnosing a dry bite. Initial subtle swelling can be more difficult to appreciate in the larger area of the leg, and the longer end of the observation period is applied for lower extremity bites. Children can also present a diagnostic dilemma as they may be unable to vocalize progression of pain. Maintain a low threshold to admit children with suspected dry bites in the lower extremity for overnight observation.

If you choose to ignore recommendations, or don’t seek care in the first place, this may occur

How do we manage rattlesnake envenomations?

First, a word on field management. Less is more here. Field therapies beyond immobilization (ice, tourniquets, extraction kits, attaching your car’s spark plug wire)6do more harm than good. The most important thing to do is get yourself or your patient to an ED, preferably one known to stock antivenom. For EMS, immobilizing the extremity in an extended position is helpful (more on this below).

Upon presentation to the ED, there a few initial steps to take. The first is pain control. Although that snakebite is unlikely to kill your patient, it is incredibly painful. Treat pain aggressively with short acting opioids like fentanyl until the nature of the envenomation is sorted out. Longer acting opioids can be used for subsequent doses. Morphine’s tendency to cause histamine reactions, which can be mistaken for an allergic reaction to antivenom, make it a suboptimal initial choice.

All rattlesnake envenomations should be treated with early immobilization and elevation of the extremity. Local tissue toxicity is the primary morbidity seen with pit viper envenomations. When an arm or leg is held down to gravity, venom will pool in the distal extremity, increasing local tissue toxicity. If the elbow is placed on a pillow and flexed at 90 degrees with the hand extended upwards, for example, venom will pool in the antecubital fossa. Elevation of the extremity and immobilization at the joints allows the venom to travel up the lymphatics and shunt more centrally, reducing morbidity. Practically speaking, this can be achieved by placing a posterior or volar slab splint, taking care to extend the splint proximal to the knee or elbow. Ensure the splint is not too tight (remember we want the venom to move more proximally) and hang it from an IV pole (arm) or prop it up on a ramp made of sheets (leg). All though this low-tech intervention sounds simple, it can be difficult to achieve due to patient compliance and requires your dedicated attention. Second to antivenom, this is arguably one of the most important interventions you can do for your patient.

by Meghan Spyres

Once you have determined that the patient has a true envenomation (swelling or any hematologic abnormality), antivenom is indicated. Crotalidae-polyvalent immune fab (Crofab®) is a sheep-derived antivenom currently approved for treatment of North American crotalid envenomations. Compared to its predecessor Wyeth antivenom, side effects from Crofab® are rare and include allergic reaction and serum sickness. A 2012 meta-analysis found incidence of each to be lower than previously thought, reported as 0.08 and 0.13, respectively.7Crofab® is a Fab fragment antibody that acts by binding venom to neutralize its effects. Crofab® helps to reverse venom-induced hematologic toxicity and to prevent further progression of the tissue toxicity. It’s important to understand that Crofab® doesn’t reverse any tissue damage that has already occurred, but it is very effective in reversing the initial hematologic toxicity. It can also help to resolve systemic effects of an envenomation. 4-6 vials are recommended as an initial bolus dose, and antivenom is re-dosed frequently until progression of edema has halted, and hematologic abnormalities have resolved (‘control’ is achieved). You should be reassessing both of these factors every hour or two in the beginning (one hour after your antivenom dose is completed, redraw labs and reassess edema). Measuring progression of edema can be difficult. Some physicians try to measure the leading edge of swelling, but this is relatively imprecise. Circumferential measurements, obtained in three places using a paper measuring tape, can offer a more objective approach. For forearm bites, circumferential measurements can be taken on the hand, forearm and proximal arm, for example. Mark the spot in each location so the same area can be measured each time. Small increases in proximal measurements are expected because the limb is elevated, and the edema will travel with gravity. An increase in distal measurements, however (assuming the limb is properly elevated and the patient didn’t convince the nurse to take splint down when you stepped away) is evidence of progressive envenomation and an indication for additional antivenom. Once control is achieved, maintenance antivenom dosing is often used (the necessity of this, however, is debated).8 Management of all rattlesnake envenomations should be done in conjunction with your local medical toxicologist or poison center if the former is not available.

by Meghan Spyresby Meghan Spyres

If a patient presents with signs of systemic toxicity, immediate resuscitation is needed. Intravenous fluids and epinephrine should be given for hypotension. Evidence of systemic toxicity alone is an indication for antivenom, and high doses (6-10 vials initial bolus) should be used. Airway protection may be required.

Pitfalls & Pointers

There are a few complications of rattlesnake envenomation that can easily lead well-meaning practitioners down a wrong path. The first is infection. Snakebites very rarely get infected, however the wound is swollen and warm, with expanding erythema, and looks not unlike an infection. Despite the appearance of the wound, prophylactic antibiotics are not indicated; these findings are a result of venom effect, not infection. Infection may be more likely (though still rare) if the patient had an extended time in the field or attempted potentially harmful interventions such as sucking the wound or using a venom extraction kit. Another misunderstood complication is compartment syndrome. Rattlesnake envenomations rarely result in compartment syndrome. The envenomation is typically superficial to the muscle compartment, and studies have shown increased blood flow to envenomated tissue.9An envenomated extremity, however, is very swollen, tense, exquisitely painful, and edema may interfere with pulse detection. To a physician less experienced with envenomations, this sounds very much like a compartment syndrome. The first step in these cases is to elevate the extremity, give antivenom, and call your local toxicologist. These interventions alone may be all you need to do. If concern for compartment syndrome persists, obtain compartment pressures and discuss the case with your surgeons, in conjunction with input from your local toxicologist. Your surgeons may not be familiar with snakebites, and we do not recommend taking these patients directly to the OR without demonstration of elevated compartment pressures. Morbidity can be increased and healing times prolonged after surgical intervention. Finally, in the absence of clinically significant bleeding, blood products are not typically indicated after rattlesnake envenomation. Platelets may drop to extremely low levels. However, giving platelets is generally not helpful as the venom will act on the donor platelets as well. Antivenom is the first line treatment for initial thrombocytopenia and/or coagulopathy after rattlesnake envenomation (recurrent hemotoxicity is another story entirely, but beyond the scope of this post). Clinically significant bleeding, despite severe hemotoxicity, is uncommon.

Of note, this month (October 2018) will mark the introduction of a new antivenom: Crotalidae equine immune F(ab’)2 (Anavip®)! This antivenom will now offer a second option for management of North American crotalid envenomations. Early studies show that Anavip® may offer reduced incidence of recurrent hemotoxicity without additional side effects.10Depending on where you work, it may end up being cheaper as well.